Gastrointestinal (GI) cancers are the most common form of cancer in humans worldwide and a leading cause of deaths in most countries. A number of growth factors are known to effect the proliferation of GI malignancies, and particular to them, in common, is the family of peptides hormones generated from the processing of preprogastrin. The maturation of preprogastrin in normal tissue involves the multistep processing of intermediate progastrin, leading to the predominant amidated forms of gastrin found in circulation; gastrin-34 (G34) and gastrin-17 (G17), known, respectively, as “big” and “little” gastrin. These hormones regulate mucosal cell growth and the (post-prandial) secretion of gastric acid, especially following ingestion of food. Progastrin and gastrin, particularly G17 and the glycine-extended form of G17 (gly-G17), have been reported to play a trophic role in GI malignancies, both in vitro and in vivo, and a number of observations support the case for targeted inhibition of these gastrins for therapeutic purposes.
Immunization against specific cancer-promoting growth factors and hormones is known to be useful in the treatment and prevention of certain cancers, especially breast cancer, lung cancer, and certain types of GI cancer. In addition, immunological approaches to the treatment and prevention of gastro-esophageal and gastro-duodenal ulcerating diseases also may be effective in the treatment of these chronic conditions.
Several treatment approaches have been employed successfully, especially ones that use targeted human or humanized monoclonal antibodies (huMAbs). Given the expense and difficulties of setting up manufacture and delivery of commercial huMAbs, however, less expensive alternative strategies are needed, particularly for the developing countries.
For GI cancers and diseases, these immunological approaches entail the generation of specific antibodies to neutralize the biological activity of disease promoting gastrointestinal peptide hormones. The antibodies required have to be specific for a particular growth factor or hormone, or hormone precursor. One or more factors or hormones can be selectively targeted to treat a particular disease.
For instance, human gastrointestinal hormone gastrin 17 (“huG17”) is involved in gastrointestinal disease processes including gastro-esophageal reflux disease, by virtue of its ability to stimulate acid and hence cause gastric and duodenal ulceration. Additionally, huG17 has been shown to stimulate the growth of some GI cancers.
Specific anti-huG17 antibodies, which are able to neutralize the action of huG17, therefore have been used in clinical trials to treat diseases in which huG17 is involved. The anti-huG17 antibodies can be administered to the patient, e.g., by passive immunization, or they can be induced in the patient by active immunization.
Similarly, although amidated gastrins were thought to be the only biologically active forms of gastrin in circulation, there now is considerable evidence that the progastrin forms of preprogastrin have proliferative potential based upon studies with human GI cancer patients and derived human cancer cell-lines. In fact, GI cancer cells are generally inefficient at processing gastrin precursors like preprogastrin and progastrin to their normal amidated form; hence, serum levels in cancer patients show much higher levels of these precursor forms of gastrin than for the normal amidated forms. It has been reported that plasma levels of progastrin but not amidated gastrin or glycine extended gastrin are significantly elevated in patients with colorectal cancer compared with those with colorectal polyps or controls (Siddheshwar et al., Gut 48: 47-52, 2001). Also progastrin, amidated gastrin, total gastrin, and glycine-extended gastrin were detected in 100%, 69%, 56%, and 44% of colorectal cancer (CRC) patient tumors, respectively (Ciccotosto et al., Gastroenterology 109: 1142-53, 1995), suggesting that cancers indeed were faulty in processing gastrins fully.